Many cancer survivors with persistent tumor disease suffer from cancer-related fatigue (CRF), which is often accompanied by depressed mood and muscle weakness. Mounting evidence indicates that fatigue and depression in cancer patients are associated with elevated plasma levels of pro-inflammatory cytokines. These cytokines have multiple target organ effects relevant to understanding the symptoms of CRF. In muscle, they suppress myogenesis and cause autophagy and degradation of myosin, resulting in loss of muscle mass and reduced contraction force. In the brain, cytokines increase expression of an enzyme which reduces synthesis of serotonin, a neurotransmitter involved in regulation of mood and locomotor activity, and increase synthesis of other tryptophan metabolites with neurodepressive effects and are associated with depressed mood. The goal of this project is to understand the effects of cytokines on the molecular pathways causing depressed mood and skeletal muscle wasting and their interaction in an animal model of CRF. Aim 1 is to test cause-and-effect relationships between cytokines, biomarkers of muscle wasting and depression in tumor-bearing mice in which fatigue is modeled as reduced voluntary wheel running activity (VWRA) and depressed mood is modeled as anhedonia, a reduced preference for sugar water. Tumor-bearing mice will be treated with minocycline to reduce cytokine expression; ibuprofen to reduce the activity of a downstream mediator of TNFa-induced skeletal muscle wasting; fluoxetine, a selective serotonin reuptake inhibitor (SSRI) , or 1-methyl tryptophan, a competitive antagonist of tryptophan metabolism. Aim 2 is to determine if physical inactivity exaggerates the effects of tumor growth on muscle function and mood in freely running versus sedentary tumor-bearing mice. Tests of muscle function will include total myosin and myosin isoforms, contraction properties, and biomarkers of muscle regeneration, autophagy and myosin degradation. Findings from the proposed project will increase our understanding of the mechanisms of fatigue and depression, which will inform more effective therapies to reduce CRF and improve the functional status of cancer survivors with persistent tumor disease.